Highlights
- •Thaimine responsive Leigh syndrome patients are genetically highly heterogeneous.
- •A large number of nucleotide variations in mt DNA are predicted to be potentially pathogenic.
- •Thiamine deficiency combined with highly heterogeneous genetic background may lead to atypical presentation of Leigh syndrome.
Abstract
In our previously published study, we cared for 165 thiamine deficient Leigh syndrome
(LS) patients who presented in acute life threatening conditions with severe neurological
abnormalities. However the molecular basis for this atypical phenotype was not explored.
This study is an effort to undermine the possible molecular defects in mitochondria
of those patients and put-forth an explanation towards this clinical presentation.
Protein coding genes of mitochondrial (mt) DNA were sequenced in total 165 LS patients
and 94 age matched controls. To understand their pathogenic significance, nucleotide
variations were also studied using various in-silico tools. Histochemical and electron microscopic analysis was also done in tissue samples
obtained from 23 patients.
We observed a very high level of genetic heterogeneity across the mt DNA of all these
patients. In the concordance of published literature we also observed a large number
of variations in ND5 gene (hot spot for LS). We also observed a total 13 nucleotide
variations across COX genes, which is otherwise not common in LS. As per in-silico analysis, many of these variations were suggested to be pathogenic. Histochemical
and electron microscopic studies also suggested the defects in the mitochondria of
these patients.
As these patients were thiamine deficient, hence we propose that genetic defects and
thiamine deficiency may together severely affect the ATP levelof these patients, leading
to acute and life threatening clinical presentation. Present study has opened up many
avenues for further research towards understanding the genetic basis and possible
role of thiamine deficiency in LS patients.
Keywords
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Article info
Publication history
Published online: July 10, 2019
Accepted:
July 8,
2019
Received in revised form:
July 3,
2019
Received:
May 20,
2019
Identification
Copyright
© 2019 Elsevier B.V. All rights reserved.
